Danon Disease Treatment & Management

  • Author: Christopher C Erickson, MD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Jan 6, 2010
 

Medical Care

Patients with Danon disease require frequent follow-up, with particular attention to the potential for atrial or ventricular arrhythmias and congestive heart failure (CHF). As is recommended in patients with hypertrophic cardiomyopathy (HCM), a ventricular septal thickness more than 30 mm is considered a risk factor for a life-threatening event, particularly in this group of patients who often have a poor prognosis for survival beyond their teenage years.[24]

An implantable cardioverter-defibrillator (ICD) may be indicated. However, in Maron’s study, all 7 patients had ICDs and 5 had lethal arrhythmias that did not convert with ICD therapy.[12] However, not all of those patients died from the arrhythmia. In addition, 4 of those 7 actually died of CHF. CHF must be treated according to the hemodynamic cause for the symptoms. For example, patients with HCM have a relatively restrictive physiology with diastolic dysfunction and should be treated accordingly (ie, improving ventricular filling, improved heart rate control, sinus rhythm maintenance, improved diastolic relaxation); whereas, those with a dilated form of cardiomyopathy tend to have a systolic dysfunction problem that may require different treatment (ie, improved afterload reduction and increased contractility).

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Surgical Care

Several surgical interventions should be considered in patients with Danon disease. The proper timing of any of these interventions is not known; however, the risk of sudden death in teenage male patients appears to be substantial. This risk may influence decisions about the timing of surgical interventions.

  • Implantable loop recorder (ILR)
  • This device is implanted under the skin to record any arrhythmias that may happen when cardiovascular symptoms occur.
    • The usual indication is an assessment of severe symptoms that occur too infrequently to be recorded by using conventional, external event recorders.
    • The battery in one device (Reveal Plus; Medtronic, Minneapolis, MN) lasts for 14 months. It can be automatically activated when the programmed parameters of the device are satisfied. It can also be activated when the patient has symptoms. An activator that the patient carries is placed over the device, and a button is pushed to activate the ILR.
  • ICD placement
    • After Danon disease and severe hypertrophic changes of the heart are diagnosed, placement of an ICD should be considered. For patients who have the dilated form of cardiomyopathy, ICDs may be indicated because of the degree of their dysfunction and their history of arrhythmias.
    • Recommendations from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) trial apply to these patients.[25]
    • Furthermore, if the degree of CHF has progressed to New York Heart Association class III or IV with maximal medical therapy (eg, beta-blockers, afterload reduction, spironolactone, diuretics), placement of a biventricular pacing system, usually a biventricular ICD, should be considered.[26]
  • Cardiac transplantation
  • Several reports mention patients with Danon disease who underwent cardiac transplantation.[17, 11, 8, 19, 12]
    • Cardiac transplant should be considered as long-term treatment because the life expectancy is short.[16] Consideration of cardiac transplantation is necessary because of the limited life expectancy of teenaged male patients, who have a high incidence of sudden death. Maron et al even recommend consideration of early transplant.[12]
    • In addition, female patients may need a cardiac transplant because they are not expected to live past their fifth decade.
    • Cardiac transplantation is a reasonable treatment for Danon disease despite the presence of muscular problems because the neurologic disability or problems are mild.
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Consultations

Because of the severe nature of this disease and the short life expectancy in male patients, extensive counseling and education with the patient and family is important. When an ICD or cardiac transplantation is contemplated, psychiatric counseling may be needed. Dealing with these issues may be particularly challenging if the patient has clinically significant mental retardation.

Consultation with a neurologist is recommended to assess the degree of skeletal myopathy and cognitive deficiencies.

Genetic consultation regarding molecular testing and genetic counseling is important.

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Diet

For the most part, no dietary restrictions are necessary for Danon disease. However, when the patient has symptoms of CHF, sodium restriction may be beneficial. Caffeine can potentially aggravate any underlying tachyarrhythmia.

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Activity

Competitive athletic activity should be restricted for individuals with Danon disease and cardiomyopathy as recommended in the 36th Bethesda Conference: Eligibility Recommendations for Competitive Athletes With Cardiovascular Abnormalities.[27] Exceptions include activities classified as I-A, which include low-intensity sports with low static and low dynamic components, such as billiards, bowling, or golf.

As for noncompetitive activity, leisurely activities (eg, using an exercise bike or treadmill, playing doubles tennis, cycling at low intensity) are permitted in patients with HCM. The premise is that patients engaging in low-intensity activities are more apt than others to respond to the onset of warning symptoms.[28]

From a neurologic standpoint, male patients with Danon disease may exercise the skeletal muscles. However, they should avoid excessive fatigue, which could cause muscle injury.[29]

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Contributor Information and Disclosures
Author

Christopher C Erickson, MD  Associate Professor, Departments of Pediatrics and Internal Medicine, Electrophysiology and Pacing, University of Nebraska College of Medicine; Associate Clinical Professor, Department of Pediatrics, Creighton University School of Medicine

Christopher C Erickson, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, American Heart Association, Cardiac Electrophysiology Society, International Society for Holter and Noninvasive Electrocardiology, and Pediatric and Congenital Electrophysiology Society

Disclosure: Nothing to disclose.

Coauthor(s)

Janice L McAllister, MD  Assistant Professor, Department of Pediatrics, University of Nebraska College of Medicine; Consulting Staff, University of Nebraska Medical Associates, St Joseph Hospital, Children's Hospital of Omaha

Janice L McAllister, MD is a member of the following medical societies: American Academy of Neurology and Child Neurology Society

Disclosure: Nothing to disclose.

Stanley J Radio, MD  Professor, Department of Pathology and Microbiology, University of Nebraska Medical Center

Stanley J Radio, MD is a member of the following medical societies: American Society for Clinical Pathology, American Society of Cytopathology, College of American Pathologists, and International Academy of Pathology

Disclosure: Nothing to disclose.

Specialty Editor Board

James Bowman, MD  Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago

James Bowman, MD is a member of the following medical societies: Alpha Omega Alpha, American Society for Clinical Pathology, American Society of Human Genetics, Central Society for Clinical Research, and College of American Pathologists

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Pharmacy Editor, eMedicine

Disclosure: Nothing to disclose.

David Flannery, MD, FAAP, FACMG  Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia

David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics and American College of Medical Genetics

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

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  2. Danon MJ, Oh SJ, DiMauro S, et al. Lysosomal glycogen storage disease with normal acid maltase. Neurology. Jan 1981;31(1):51-7. [Medline].

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  4. Sugie K, Yamamoto A, Murayama K, et ak. Clinicopathological features of genetically confirmed Danon disease. Neurology. Jun 25 2002;58(12):1773-8. [Medline].

  5. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults. Circulation. Aug 15 1995;92(4):785-9. [Medline].

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  8. Yang Z, McMahon CJ, Smith LR, et al. Danon disease as an underrecognized cause of hypertrophic cardiomyopathy in children. Circulation. Sep 13 2005;112(11):1612-7. [Medline].

  9. Riggs JE, Schochet SS, Gutmann L, et al. Lysosomal glycogen storage disease without acid maltase deficiency. Neurology. Jul 1983;33(7):873-7. [Medline].

  10. Byrne E, Dennett X, Crotty B, et al. Dominantly inherited cardioskeletal myopathy with lysosomal glycogen storage and normal acid maltase levels. Brain. Jun 1986;109 (Pt 3):523-36. [Medline].

  11. Lacoste-Collin L, Garcia V, Uro-Coste E, et al. Danon's disease (X-linked vacuolar cardiomyopathy and myopathy): a case with a novel Lamp-2 gene mutation. Neuromuscul Disord. Nov 2002;12(9):882-5. [Medline].

  12. Maron BJ, Roberts WC, Arad M, Haas TS, Spirito P, Wright GB. Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy. JAMA. Mar 25 2009;301(12):1253-9. [Medline].

  13. van der Kooi AJ, van Langen IM, Aronica E, van Doorn PA, Wokke JH, Brusse E. Extension of the clinical spectrum of Danon disease. Neurology. Apr 15 2008;70(16):1358-9. [Medline].

  14. Fanin M, Nascimbeni AC, Fulizio L, Spinazzi M, Melacini P, Angelini C. Generalized lysosome-associated membrane protein-2 defect explains multisystem clinical involvement and allows leukocyte diagnostic screening in Danon disease. Am J Pathol. Apr 2006;168(4):1309-20. [Medline].

  15. Spinazzi M, Fanin M, Melacini P, Nascimbeni AC, Angelini C. Cardioembolic stroke in Danon disease. Clin Genet. Apr 2008;73(4):388-90. [Medline].

  16. Prall FR, Drack A, Taylor M, Ku L, Olson JL, Gregory D. Ophthalmic manifestations of Danon disease. Ophthalmology. Jun 2006;113(6):1010-3. [Medline].

  17. Dworzak F, Casazza F, Mora M, et al. Lysosomal glycogen storage with normal acid maltase: a familial study with successful heart transplant. Neuromuscul Disord. May 1994;4(3):243-7. [Medline].

  18. Laforet P, Charron P, Maisonobe T, et al. Charcot-Marie-Tooth features and maculopathy in a patient with Danon disease. Neurology. Oct 26 2004;63(8):1535. [Medline].

  19. Echaniz-Laguna A, Mohr M, Epailly E, et al. Novel Lamp-2 gene mutation and successful treatment with heart transplantation in a large family with Danon disease. Muscle Nerve. Mar 2006;33(3):393-7. [Medline].

  20. Froissart R, Maire I. Danon Disease. Orphanet Encyclopedia. 2002;[Full Text].

  21. Konecki DS, Foetisch K, Zimmer KP, Schlotter M, Lichter-Konecki U. An alternatively spliced form of the human lysosome-associated membrane protein-2 gene is expressed in a tissue-specific manner. Biochem Biophys Res Commun. Oct 13 1995;215(2):757-67. [Medline].

  22. Furuta K, Yang XL, Chen JS, Hamilton SR, August JT. Differential expression of the lysosome-associated membrane proteins in normal human tissues. Arch Biochem Biophys. May 1 1999;365(1):75-82. [Medline].

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  24. Spirito P, Bellone P, Harris KM, Bernabo P, Bruzzi P, Maron BJ. Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med. Jun 15 2000;342(24):1778-85. [Medline].

  25. [Guideline] Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. Jan 20 2005;352(3):225-37. [Medline].

  26. Young JB, Abraham WT, Smith AL, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA. May 28 2003;289(20):2685-94. [Medline].

  27. Maron BJ, Ackerman MJ, Nishimura RA, Pyeritz RE, Towbin JA, Udelson JE. Task Force 4: HCM and other cardiomyopathies, mitral valve prolapse, myocarditis, and Marfan syndrome. J Am Coll Cardiol. Apr 19 2005;45(8):1340-5. [Medline].

  28. Maron BJ, Chaitman BR, Ackerman MJ, et al. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation. Jun 8 2004;109(22):2807-16. [Medline].

  29. Stuberg WA. Muscular dystrophy and muscular atrophy. In: Campbell SK, Vander Linden DW, Palisano RJ, eds. Physical Therapy for Children. 3rd ed. Philadelphia, Pa: WB Saunders; 2005:421-52.

  30. Maron BJ, Estes NA 3rd, Maron MS, Almquist AK, Link MS, Udelson JE. Primary prevention of sudden death as a novel treatment strategy in hypertrophic cardiomyopathy. Circulation. Jun 17 2003;107(23):2872-5. [Medline].

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Echocardiogram of a patient with Danon disease and severe hypertrophy. The septum is between the arrows. Note the asymmetry between the septum and the posterior wall of the left ventricle. Also see Media files 2-3. Calibration markings are in centimeters. Ao = ascending aorta just above the aortic valve; LV = left ventricle; LVPW = left ventricular posterior wall.
Echocardiogram, short-axis view in diastole, in the same patient as in Media files 1 and 3. Because of the degree of hypertrophy, the cavitary volume is smaller than normal. Calibration markings are in centimeters. Ao = ascending aorta just above the aortic valve; LV = left ventricle; LVPW = left ventricular posterior wall.
Echocardiogram, short-axis view in systole, in the same patient as in Media files 1-2. Note the increased thickening of the septum. Calibration markings are in centimeters. Ao = ascending aorta just above the aortic valve; LV = left ventricle; LVPW = left ventricular posterior wall.
Horizontal ventricular sections of the heart from 16-year-old male adolescent with Danon disease obtained after orthotopic cardiac transplantation. Massive hypertrophy is present (heart weight, 785 g), with diffuse severe fibrosis and marked ventricular dilatation.
Myocyte hypertrophy and vacuolization with interstitial fibrosis in the myocardium of a heart removed during cardiac transplantation (periodic acid-Schiff [PAS] stain; original magnification, X400).
Electron photomicrograph shows autophagic vacuoles with glycogen in a heart removed during cardiac transplantation (uranyl acetate and Reynolds lead citrate; original magnification X20,000).
Electron photomicrograph shows increased amounts of intermyofibrillar glycogen in the myocardium (uranyl acetate and Reynolds lead citrate; original magnification, X13,000).
 
 
 
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